Intrinsic apoptosis is a cell death mechanism that is an important host response to combat pathogen infection. While traditionally thought to be immunologically silent, recent studies have demonstrated crosstalk between intrinsic apoptotic cell death signalling and inflammation via caspase-3/-7-dependent NLRP3 inflammasome activation. However, little is known about the regulation of intrinsic apoptosis during bacterial infection, and whether this inflammatory crosstalk is protective. Moreover, whether inducing cell death in infected macrophages, which act as a replicative niche for a growing number of antimicrobial resistant bacteria, can be harnessed to promote pathogen clearance remains unclear.
It is well established that bone marrow derived macrophages (BMDMs) rely on the BCL-2 family pro-survival proteins BCL-XL and MCL-1 for their survival. Our unpublished findings also reveal an essential role for the inducible, short-lived, BCL-2 family member BCL2A1 (A1) in delaying apoptosis upon Gram-negative bacterial LPS exposure and BCL-XL and MCL-1 targeting. Interestingly, we now find that targeting BCL-2, in conjunction with MCL-1 inhibition and A1 loss, also triggers late stage cell death and NLRP3 inflammasome activity in LPS-primed macrophages. Finally, we show the potential physiological relevance of A1 in limiting cell death and inflammation using the Gram-negative intracellular bacteria Legionella pneumophila. Collectively, our data suggest that pathogens may modulate BCL-2 family member expression and function to elude the host immune system.